Mucous membranes provide a protective layer on the surface of several body cavities, such as the oral cavity, the nasal cavity, the gastrointestinal and respiratory tracts, the vagina, and the bladder. Cells within or glands adjacent to these membranes secrete mucus, a fluid or gel primarily composed of water, lipids, inorganic salts and mucin glycoproteins, which serve to form a protective barrier to inhibit passage of harmful materials to the underlying tissue. There are several diseases and disorders of these mucosal surfaces which can result in severe pain, irritation, erythema, and/or ulceration. Examples of such diseases in the oral cavity include aphthous ulcers, bullous pemphigoid, oral lichen planus, and oral mucous membrane contact dermatitis; examples of diseases of the nasal mucous membrane include sinusitis and rhinitis; an example for the bladder is interstitial cystitis. Certain diseases such as Behçet syndrome, can affect the mucocutaneous membranes of several regions of the body. Many other ulcerative mucocutaneous diseases are known. There are also painful ulcerative disorders of mucosal surfaces which result as an adverse side-effect in certain therapies, such as chemotherapy and radiation therapy. Examples of such side-effects include mucositis, esophagitis, and radiation proctitis.
The following section provides a brief description of these conditions
Aphthous Ulcers
Aphthous ulcers (also known as aphthous stomatitis and canker stores) are benign open sores in the mouth, which appears as a painful white or yellow sore (ulcer) surrounded by a bright red area. Aphthous ulcers can be categorized into three groups:
minor aphthous ulcers, the most common type, which recur in crops of 1 to 5 lesions, are less than 1 cm in diameter each, and usually affect the lips, buccal mucosa, mucobuccal and mucolabial sulci, and tongue;
major aphthous ulcers, which are greater than 2 cm in diameter, begin as solitary nodules, and subsequently destroy deeper tissue, resulting in scarring that affects the movable oral mucosa and posterior mucosal surfaces; and
herpetiform ulcers, which are recurrent, multiple (10 to 100), shallow, pinpoint lesions 1 to 2 mm in diameter that may affect any part of the mucosa. The cause for any of the three types is not known, although autoimmune mechanisms are suspected.
The cause is unknown. There may be an inherited predisposition to their development. There may also be an immune system link. Ulcers may develop in response to mouth injury such as dental procedures or aggressive tooth cleaning. They may occur at the site of a bite when the tongue or cheek is bitten. They can also triggered by stress, dietary deficiencies (especially iron, folic acid, or vitamin B12), menstrual periods, hormonal changes, food allergies, and similar situations. They may occur with no identifiable cause. Canker sores usually appear on nonkeratinized mouth tissue including the inner surface of the cheeks and lips, tongue, soft palate, and the base of the gums. They usually begin with a tingling or burning sensation, followed by a red spot or bump that ulcerates. Pain spontaneously decreases in 7 to 10 days, with complete healing in 1 to 3 weeks. Occasionally, a severe occurrence may be accompanied by nonspecific symptoms of illness such as fever or malaise. Recurrence is common and may continue for years (sources: WebMD, Rakel: Conn's Current Therapy 2000, 52nd ed).
Aphthous ulcers are occasionally associated with macrocytic anemias or gluten-sensitive enteropathy and may become more frequent and severe in association with human immunodeficiency virus (HIV) infection (source: Goldman: Cecil Textbook of Medicine, 21st Ed.)
Behçet Syndrome
Behcet's disease is a chronic multisystem disease characterized by oral and genital aphthae, arthritis, cutaneous lesions, and ocular, gastrointestinal, and neurologic manifestations. It was first described by the Turkish dermatologist Hulusi Behcet in 1937 as “recurrent oral aphthous ulcers, genital ulcers, and ‘hypopyon-uveitis.’” The diagnosis of Behcet's disease is based on clinical criteria as established by O'Duffy and Goldstein and the International Study Group. Complex aphthosis is the presence of almost constant, multiple oral or oral and genital aphthae in the absence of systemic manifestations. These patients must be distinguished from those with Behcet's disease.
The prevalence of Behcet's disease is higher in the Middle East and Japan where it is approximately 1 in 1000. The disease is far less common in northern Europe, the United States, and the United Kingdom. The mean age of onset ranges from the mid to late 20s to the fourth decade, according to several series, with a slightly higher male to female ratio. It is relatively rare in children and the elderly. Behcet's disease is also uncommon among black Africans who, when they are affected, tend to have more mucocutaneous features. Although a definitive pattern of inheritance has not been elucidated, familial cases have been reported. Patients with complex aphthosis are probably a subset of patients with recurrent aphthous stomatitis, which is defined as the recurrence of 1 or more painful oral ulcers at intervals ranging from days to months. The prevalence of recurrent aphthosis ranges from 5% to 66%. Onset may occur in childhood or adolescence and some patients experience a decrease in frequency with advancing age. (source: J. V Ghate and J. L. Jorizzo, “Behcet's disease and complex aphthosis”, Journal of the American Academy of Dermatology, 1999, 40(1), 1-18.)
Bullous Pemphigoid
Bullous pemphigoid (BP) is an autoimmune, subepidermal blistering disease. The antigenic targets are components of the hemidesmosome; the 230-kD bullous pemphigoid antigen 1 and the 180-kD bullous pemphigoid antigen 2. It commonly affects patients in their seventh decade. About 40% of patients will experience oral involvement during the course of their disease.
The mainstay of treatment for BP is systemic corticosteroids. Bullous pemphigoid is usually exquisitely sensitive to these drugs, but significant side effects in a predominantly elderly patient population limits their long-term use at therapeutic doses. Steroid-sparing agents, such as dapsone, methotrexate, and azathioprine, have been used successfully. In addition, tetracycline and niacinamide have been shown to be effective, and this combination is frequently tried first to avoid toxicity from other drugs. (source: J. L. Popovsky and C. Camisa, “New and emerging therapies for diseases of the oral cavity”, Dermatologic Clinics, 2000, 18(1), 113-125.).
Chemical and Radiation Cystitis
The term ‘cystitis’ covers a range of disorders commonly known “painful bladder” disease in which sufferers bladder and/or pelvic pain and irritative voiding symptoms (urgency, frequency, nocturia, dysuria). There are a variety of known causes, which includes the damaging side-effects of radiation therapy to the lower abdomen, and cytotoxic agents and/or their metabolites as they pass through the bladder following renal clearance.
Cyclophosphamide (Cytoxan), the most commonly used oxazaphosphorine, is an alkylating agent first used in the treatment of malignant tumors in Europe in 1957. Cyclophosphamide still has a role in the treatment of solid tumors and lymphomas, as well as benign inflammatory states, Wegener's granulomatosis and rheumatoid arthritis being the most common. Other oxazaphosphorines—ifosfamide, trofosphamide, and sufosfamide—have been used since the 1970s for the treatment of solid malignancies and lymphomas. Dose-limiting toxicity with these compounds is usually urinary tract toxicity.
Subsequent to treatment with these compounds, urinary symptoms including frequency, urgency, dysuria, and nocturia develop in as many as 24% of patients treated with oral Cytoxan.
Bladder pathology has been attributed to toxic metabolites of these compounds. Cyclophosphamide is broken down by hepatic microsomal cells to hydroxycyclophosphamide; then by target cells to aldophosphamide; and then to phosphoramide mustard, the active antineoplastic metabolite, and acrolein, which has no significant antitumor activity. Similarly, ifosfamide is metabolized to iphosphoramide mustard and acrolein. Urinary excretion of acrolein is believed to be the major source of urothelial toxicity. Most normal cells are able to break down the toxic metabolites and diminish their effect. Glutathione is a naturally occurring thiol that can confer such protection in most cells, but is present in low levels in urine.
Oxazaphosphorine toxicity has been demonstrated in several animal models with their systemic administration and by instillation of their normal metabolic products directly into the bladder. Urine from animals given these agents, when placed in other animal bladders, will reproduce these findings, while instillation of cyclophosphamide will not. Electron microscopy suggests the initial toxic effect is disruption of the plasma membrane and cytoplasmic matrix.
Bladder damage from these compounds is cumulative, and is generally dose related. “Cyclophosphamide cystitis” occurs frequently and early following intravenous (IV) therapy, especially dose-intensive regimens. Cystitis usually takes weeks to develop after oral treatment, but has been seen after as little as one dose. Fibrosis has been found in as many as 25% of children receiving high-dose cyclophosphamide. Severe hematuria and telangiectasia are more common in these patients. Oxazaphosphorine cystitis is potentiated by prior pelvic radiation.
Cystoscopy may reveal a tumor or changes compatible with cyclophosphamide cystitis. Acutely diffuse inflammation is seen. Chronic changes include a pale bladder mucosa with telangiectasia. Areas of edema can be present with patchy hemorrhagic areas that stain with methylene blue, an indicator of mucosal injury. Biopsies reveal hyperemia, hemorrhage, edema, mucosal thinning, and ulceration of the urothelium. Necrosis of mucosa, muscle, and small arterioles and telangiectasia can be present. Atypia can be prominent, and abundant mitoses often occur. These findings are similar to those seen after radiation therapy.(source: DeVita: Cancer: Principles and Practice of Oncology, 5th ed., Copyright© 1997 Lippincott-Raven Publishers).
Erythema Multiforme
Erythema multiforme often affects the oral cavity and is frequently recurrent. The classic cutaneous findings are targetoid lesions symmetrically distributed over the trunk and extremities. Studies show that as many as 70% of patients develop oral lesions, which are extremely painful and often debilitating. In more than 60% of patients, the attacks followed an episode of herpes simplex virus (HSV) infection. Acyclovir or one of the newer antiviral agents can be used to suppress recurrent HSV outbreaks and to prevent recurrent erythema multiforme. The current recommendations for daily suppression of HSV are acyclovir (400 mg twice daily), famciclovir (250 mg twice daily), or alacyclovir (500 mg daily). Suppressive doses are to be used for patients who experience more than six episodes a year of HSV or HSV-induced erythema multiforme.
Azathioprine (Imuran) can also be used to treat erythema multiforme. It should be used for patients who have severe mucosal involvement or in whom lesions continue to occur despite HSV suppression. In one study, 11 patients with severe disease failed to respond to acyclovir, dapsone, or antimalarials, but all cleared with azathioprine, 100 to 150 mg daily. Response was dose-dependent, and the condition relapsed when therapy was discontinued. Thalidomide has also been shown to be effective for recurrent erythema multiforme. (source: J. L. Popovsky and C. Camisa, “New and emerging therapies for diseases of the oral cavity”, Dermatologic Clinics, 2000, 18(1), 113-125.)
Esophagitis
Esophagitis is a side-effect of the radiation therapy of the chest when the esophagus receives an unavoidable significant radiation dose.
Acute side effects occurring during the course of radiotherapy are organ specific and related to the fractionation scheme, total dose, and use of sequential or concomitant chemotherapy or radiosensitizers. They typically manifest in the second to third week of treatment. A significant concern of combined therapy is the increased toxicity, which may potentially outweigh the benefit from both modalities.
Most patients do not develop symptoms related to lung irradiation until the end of treatment. Some patients complain of a dry, nonproductive cough secondary to radiation effect on the trachea or bronchi. This reaction can last for several weeks after the completion of treatment. Radiation may also induce acute esophagitis during the course of therapy, which typically occurs during the second through fourth weeks of treatment, as well as shortly after completion. Chemotherapy and radiosensitizers appear to accelerate the onset and severity of symptoms. Agents such as 5-fluorouracil, doxorubicin, cisplatin, and mitomycin enhance the effect of radiation with regard to the esophagus. In general, acute esophagitis resolves shortly after the completion of radiotherapy, with few patients progressing to chronic esophagitis. Esophagitis presents with mild to severe swallowing difficulty requiring diet modification and nonnarcotic or narcotic analgesics, depending on severity. (source: DeVita: Cancer: Principles and Practice of Oncology, 5th ed)
Interstitial Cystitis
Interstitial cystitis (IC) has only recently been recognized as a major health problem. It encompasses a major portion of the “painful bladder” disease complex, which includes a large group of urologic patients with bladder and/or pelvic pain, irritative voiding symptoms (urgency, frequency, nocturia, dysuria), and negative urine cultures. Painful bladder diseases with a well-known cause include radiation cystitis, cyclophosphamide cystitis, cystitis caused by microorganisms that are not detected by routine culture methodology, and systemic diseases affecting the bladder.
One problem with defining IC is that the symptoms are in reality an exaggeration of normal sensations. Urinary frequency patterns can be related to fluid intake and age, and the signal or urge to void is considered an unpleasant or painful sensation by most persons. With no pathognomonic findings on pathologic examination, IC is truly a diagnosis of exclusion. It may have multiple causes and represent a final common reaction of the bladder to different types of insult. Thus, issues of definition are critical. To understand the current way IC is defined and how this came to be, a look back in time is helpful.
In 1987 there were 43,500 (perhaps up to 90,000) diagnosed cases of IC in the United States, approximately twice the prevalence in Finland found by Oravisto 12 years earlier. More interesting, women who were diagnosed by sampled urologists as actually having IC represented only 20% of the cases presenting with symptoms (chronic painful bladder, sterile urine) that were suggestive of this disease. On the basis of these data, from 250,000 to almost 500,000 patients in the United States might have had IC in 1987, depending on the assumptions used.
The median age of onset is 40 years.
Up to 50% of patients experience spontaneous remissions probably unrelated to treatment with a duration ranging from 1 to 80 months (mean 8 months).
Patients with IC are 10 to 12 times more likely than controls to report childhood bladder problems.
The time from symptom onset to diagnosis varied from 24 months for the patients most recently diagnosed to 51 months for members of the Interstitial Cystitis Association.
Taking the prevalence figure of 44,000, the IC-related incremental medical care cost in the United States was $116.6 million in 1987 and IC-related lost economic production was $311.7 million.
Intravesical lavage with one of a variety of preparations remains the standard treatment against which other treatments must be measured. A mainstay of the treatment of IC is the intravesical instillation of DMSO. DMSO is a product of the wood pulp industry and a derivative of lignin. It has exceptional solvent properties and is freely miscible with water, lipids, and organic agents. Pharnacologic properties include membrane penetration, enhanced drug absorption, anti-inflammatory properties, analgesic properties, collagen dissolution, muscle relaxation, and mast cell histamine release. In vitro effects on bladder function belie its positive effects in vivo. (source: Walsh: Campbell's Urology, 7th ed., Copyright© 1998 W. B. Saunders Company).
Mucositis
Oral mucositis is a significant problem in patients receiving chemotherapy or radiation therapy. Estimates of oral mucositis in cancer therapy range from 40% of those receiving standard chemotherapy to 76% of bone marrow transplant patients. Virtually all patients who receive radiation therapy to the head and neck area develop oral complications. Mucositis is not only painful, but it also can limit adequate nutritional intake and decrease the willingness of patients to continue treatment. More severe mucositis with extensive ulceration may require costly hospitalizations with parenteral nutrition and narcotics. Mucositis diminishes the quality of life and may result in serious clinical complications. A healthy oral mucosa serves to clear microorganisms and provides a chemical barrier that limits penetration of many compounds into the epithelium. A mucosal surface that is damaged increases the risk of a secondary infection and may even prove to be a nidus for systemic infection. Mucositis may result in the need to reduce dosage in subsequent chemotherapy cycles or to delay radiation therapy, which may ultimately affect patient response to therapy.
Normally, cells of the mouth undergo rapid renewal over a 7- to 14-day cycle. Both chemotherapy and radiation therapy interfere with cellular mitosis and reduce the ability of the oral mucosa to regenerate. Cancer chemotherapeutic drugs that produce direct stomatotoxicity include the alkylating agents, antimetabolites, natural products, and other synthetic agents such as hydroxyurea and procarbazine hydrochloride. Typical sequelae of these cytotoxic agents include epithelial hyperplasia, collagen and glandular degeneration, and epithelial dysplasia. Mucositis is an inevitable side effect of radiation. The severity of the mucositis is dependent on the type of ionizing radiation, the volume of irradiated tissue, the dose per day, and the cumulative dose. As the mucositis becomes more severe, pseudomembranes and ulcerations develop. Poor nutritional status further interferes with mucosal regeneration by decreasing cellular migration and renewal.
Direct stomatotoxicity is usually seen 5 to 7 days after the administration of chemotherapy or radiation therapy. In the nonmyelosuppressed patient, oral lesions heal within 2 to 3 weeks. The nonkeratinized mucosa is most affected. The most common sites include the labial, buccal, and soft palate mucosa, as well as the floor of the mouth and the ventral surface of the tongue. Clinically, mucositis presents with multiple complex symptoms. It begins with asymptomatic redness and erythema and progresses through solitary white elevated desquamative patches that are slightly painful to contact pressure. Following this large, acutely painful contiguous pseudomembranous lesions will develop with associated dysphagia and decreased oral intake. Histopathologically, edema of the retepegs is noted, along with vascular changes that demonstrate a thickening of the tunica intima with concomitant reduction in the size of the lumen and destruction of the elastic and muscle fibers of the vessel walls. The loss of the epithelial cells to the basement membrane exposes the underlying connective tissue stroma with its associated innervation, which, as the mucosal lesions enlarge, contributes to increasing pain. Oral infections, which may be due to bacteria, viruses, or fungal organisms, can further exacerbate the mucositis as well as lead to systemic infections. If the patient develops both severe mucositis and thrombocytopenia, oral bleeding may occur that is very difficult to treat.
A mucositis grading system gives the physician the ability to assess the severity of the mucositis in terms of both the pain and the patient's ability to maintain adequate nutrition so that a treatment plan can be appropriately constructed. There are many different grading systems; most are based on two or more clinical parameters, including erythema, pain, and problems with eating. An example of a common grading system is that proposed by the National Cancer Institute, which uses a numbering scale of 0 to 4. Grade 0 means no mucositis; grade 1, the patient has painless ulcers, erythema, or mild soreness; grade 2, the patient has painful erythema, edema, or ulcers but can eat; grade 3, the patient has painful erythema, edema, or ulcers and cannot eat; and grade 4, the patient requires parenteral or enteral support.
A standardized approach for the prevention and treatment of chemotherapy- and radiation-induced mucositis is essential; unfortunately, the efficacy and safety of most of the regimens have not been established. The prophylactic measures usually employed for the prevention of mucositis include chlorhexidine gluconate (Peridex), saline rinses, sodium bicarbonate rinses, acyclovir, amphotericin, and ice. Regimens commonly used for the treatment of mucositis and its associated pain include a local anesthetic such as lidocaine or Dyclone, Maalox or Mylanta, diphenhydramine (Benadryl), nystatin, or sucralfate. These agents are either used alone or in different combinations of the above medications made into a mouthwash. Other agents used less commonly include Kaopectate, allopurinol, vitamin E, beta-carotene, Kamillosan liquid, aspirin, antiprostaglandins, prostaglandins, MGI 209 (marketed as Oratect Gel), silver nitrate, and antibiotics. Oral and sometimes parenteral narcotics are used for pain relief. A new method utilizing capsaicin is currently under study to help relieve the pain. (source: DeVita: Cancer: Principles and Practice of Oncology, 5th ed., Copyright© 1997 Lippincott-Raven Publishers).
Oral Lichen Planus
Lichen planus (LP) is a common, idiopathic skin disorder affecting approximately 2% of the adult US population. Although its behavior on the skin is predictable and manageable using topical corticosteroids, oral lichen planus (OLP) has a more variable clinical course and is less responsive to topical corticosteroid therapy. There are multiple clinical presentations of OLP, and the disorders in some of these clinical forms can mimic many other types of oral lesions. Furthermore, some authors believe that certain clinical types of OLP may have a premalignant nature. Various drugs, topical and systemic, have been shown to induce lichenoid lesions through antigenic mechanisms.
There is even good evidence emerging that amalgam and dental plaque can act as antigens to induce OLP in some patients. The plaque form of OLP is seen more often in smokers. Women appear to be affected more often than men. Not all persons who develop skin lesions develop OLP at the same time and vice versa. Those patients who develop skin lesions only are usually free of their LP in approximately 18 months; however, patients with OLP may have their lesions for up to 20 years. Thus, management strategies for the patient with OLP are markedly different than for its skin surface counterpart.
The most common oral presentation of LP is the reticular form. These lesions appear as raised white, linear striations that often interlace in what is termed striae of Wickham. These striations are almost pathognomonic of the disorder. It should be noted that these linear lesions also accompany the erosive form of OLP and occur at the periphery of the eroded area. This is a significant diagnostic clue in the evaluation of the erosive type. The reticular form usually is observed on the buccal mucosa, often bilaterally. Several authors have noted that these lesions are adjacent to gold or silver amalgam restorations in many cases. The lesions are asymptomatic.
The bullous form of OLP is uncommon, perhaps because the oral cavity is a very active region. The functions of chewing, swallowing, and speaking probably do not allow the bulla to remain intact for very long. The size of these lesions is variable, from a few millimeters to several centimeters. The plaque type of OLP appears as a nondescript leukoplakia that needs to be biopsied if no other diagnosis can be made for the lesion. These lesions appear as multiple diffuse, raised white plaques commonly on the buccal mucosa and tongue. Silverman et al have determined that patients with this form of LP tend to be smokers. This may place them at risk for transformation to dysplasia or carcinomatous change.
The atrophic form of OLP can be seen concomitantly with the erosive or reticular forms. This is frequently the type of OLP seen on the gingiva of patients, commonly referred to as desquamative gingivitis. These lesions are symptomatic. The patient may complain of burning and pain while brushing. Because dental plaque has been implicated as a possible antigen, the patient will need to see a dentist for professional maintenance following initial corticosteroid treatment of the lesions.
Erosive LP is the most painful form of OLP. As stated previously, these erosions are seen frequently with the reticular form adjacent to the area. Atrophic or plaque forms may be seen less commonly. Erosive LP may mimic oral cancer, erythema multiforme, lupus erythematosus, and candidiasis. Many drugs can produce lesions that look like erosive LP clinically. (source: D. A. Miles and M. M. Howard, “Disorders affecting the oral cavity: Diagnosis and management of oral lichen planus”, Dermatologic Clinics, 1996, 14(2), 281-290.)
Pemphigus
Pemphigus is a rare, autoimmune blistering disease. Of the various forms of pemphigus, pemphigus vulgaris and paraneoplastic pemphigus affect the oral mucosa with regularity. The antigenic targets in pemphigus are components of the desmosome. Binding of autoantibodies to these antigenic proteins, desmogleins and desmoplakins, leads to dissolution of intercellular adhesion with resultant blister formation. Activity of the disease correlates with titers of pemphigus antibody, which can be detected in the serum of patients with the disease by indirect immunofluorescence testing.
Pemphigus was often a fatal disease before the use of systemic corticosteroids. It has a chronic course, and control of the disease becomes more difficult with subsequent flares. The basis of treatment is immunosuppression to decrease antibody synthesis. Relapses may occur when immunosuppressive drugs are tapered. Paraneoplastic pemphigus remains a very difficult disease to treat and continues to have very high mortality rates.
Historically, therapy for pemphigus was initiated with very high doses of prednisone. This initial high dosage proved to have so many adverse effects that in one early study 8% of patients died from complications of treatment (mainly infections) rather than from pemphigus. The authors recommend that pemphigus initially be treated with prednisone, 60 to 80 mg daily, and generally no more than 100 mg daily. Studies have shown that this dosage is usually as effective as higher doses. If there is no response, but the patient remains stable, the authors recommend adding a second immunosuppressive agent rather than increasing the dose of steroids. Although there are no good controlled studies to support this practice, it is also being followed in the treatment of organ transplant rejection to decrease morbidity from corticosteroids. In patients in whom the disease must be rapidly controlled, higher doses of prednisone may be required to stabilize the patient.
Successful treatment of pemphigus has been achieved with prednisone in combination with azathioprine, cyclosporine, cyclophosphamide, dapsone, and gold sodium thiomalate.
Fleischli et al report the successful treatment of pemphigus vulgaris with pulse intravenous cyclophosphamide. Six of nine patients responded to therapy, and two patients achieved remission of skin lesions. One patient was able to discontinue prednisone completely. Two patients died of cardiac complications despite improvement of their skin disease. One patient developed sepsis that was successfully treated with intravenous antibiotics. The investigators concluded that pulse cyclophosphamide may be a useful adjunctive treatment for recalcitrant disease. Long-term side effects such as secondary malignancy may be less likely to result from this treatment than from perorally administered cyclophosphamide because of the lower cumulative doses. Intravenously administered cyclophosphamide should be reserved for patients with severe, recalcitrant disease because of the serious complications that may occur during therapy. (source: J. L. Popovsky and C. Camisa, “New and emerging therapies for diseases of the oral cavity”, Dermatologic Clinics, 2000, 18(1), 113-125.)
Radiation Proctitis
Acute complications of pelvic radiation occur with distinct clinical courses and pathologic manifestations. The most frequent serious complication of pelvic radiation is small bowel damage, including thrombocytopenia, leukopenia, dysuria, and effects on the small bowel (diarrhea, abdominal cramping, and increased bowel frequency) and large bowel (acute proctitis, tenesmus, bloody and/or mucus discharge). Sigmoidoscopy during treatment normally reveals an inflamed, edematous, and friable rectal mucosa consistent with acute radiation proctitis. These symptoms are usually transient and resolve within a few weeks following the completion of radiation therapy. They appear to be a function of the dose rate and fraction size rather than the total dose. The mechanism is primarily the depletion of actively dividing cells in what is otherwise a stable cell renewal system. In the small bowel, loss of the mucosal cells results in malabsorption of various substances including fat, carbohydrate, protein, and bile salts. The management of bowel-related complications usually involves the use of diphenoxylate and/or narcotics. The bowel mucosa usually recovers in 1 to 3 months following the completion of radiation. (source: DeVita: Cancer: Principles and Practice of Oncology, 5th ed., Copyright© 1997 Lippincott-Raven Publishers).
Ulcerative Colitis
Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, are chronic inflammatory diseases of the gastrointestinal tract. They are diagnosed by a set of clinical, endoscopic, and histologic characteristics, but no single finding is absolutely diagnostic for one disease or the other. Moreover, some patients have a clinical picture that falls between the two diseases and are said to have indeterminate colitis.
The inflammatory response in ulcerative colitis is largely confined to the mucosa and submucosa, but in Crohn's disease the inflammation extends through the intestinal wall from mucosa to serosa. Ulcerative colitis is confined to the colon, and colectomy is a curative procedure. Crohn's disease, in contrast, can involve any part of the gastrointestinal tract, although the distal small bowel and the colon are most commonly involved. Resection of the inflamed segment is not curative in Crohn's disease, and inflammation is likely to recur.
In ulcerative colitis, inflammation begins in the rectum, extends proximally a certain distance, and then abruptly stops, with a clear demarcation between involved and uninvolved mucosa. In mild disease, there are superficial erosions, whereas in more severe disease, ulcers may be large but superficial, penetrating the muscularis mucosa only in very severe disease. Inflammatory polyps or pseudopolyps may be present. Most of the pathologic findings in ulcerative colitis are limited to the mucosa and submucosa; the muscularis propria is affected only in fulminant disease. Active ulcerative colitis is marked by neutrophils in the mucosa and submucosa and clumps of neutrophils in crypt lumens (crypt abscesses). There is mucus depletion, mucosal edema, and vascular congestion with focal hemorrhage. In addition to signs of acute activity, there are also signs of chronicity, with lymphoid aggregates, plasma cells, mast cells, and eosinophils in the lamina propria.
The dominant symptom in ulcerative colitis is diarrhea, which is usually associated with blood in the stool. Bowel movements are frequent but small in volume as a result of irritability of the inflamed rectum. Urgency and fecal incontinence may limit the patient's ability to function in society. Other symptoms include fever and pain, which may be in either lower quadrant or in the rectum. Systemic features—fever, malaise, and weight loss—are more common if all or most of the colon is involved and may have a greater effect than diarrhea on the patient's ability to function. Some patients, especially elderly persons, complain of constipation rather than diarrhea because rectal spasm prevents the passage of stool. The initial attack of ulcerative colitis may be fulminant with bloody diarrhea, but more commonly the disease begins indolently, with non-bloody diarrhea progressing to bloody diarrhea Ulcerative colitis can present initially with any extent of anatomic involvement, from disease confined to the rectum to pancolitis. Most commonly, ulcerative colitis follows a chronic intermittent course with long periods of quiescence interspersed with acute attacks lasting weeks to months; however, a significant percentage of patients suffer a chronic continuous course. (source: Goldman: Cecil Textbook of Medicine, 21st Ed).
In the diseases and disorders listed above, there are either no adequate treatment options, or the treatments, while demonstrating success, may lead to the development of significant adverse side-effects.
It is an aim of the present invention to provide viscous, mucoadhesive liquid formulations to be used for the prevention and treatment of mucocutaneous disorders. The formulation may be used with or without one or more active pharmaceutical agents. These formulations are especially beneficial in diseases and conditions in which a wide area of the mucosal surface requires treatment, but the formulations may also be used in treating small areas of the mucosal surface.
In order that mucocutaneous disorders are treated effectively, it is preferred that the lesion is in contact with the liquid, mucoadhesive formulation for the period of time required to derive benefit. To grant such benefit, this invention describes mucoadhesive, viscous liquid formulations which may or may not contain one or more pharmaceutically active ingredients. The liquid can readily be applied to the affected region of the mucosa by methods known in the art, while the high viscosity and mucoadhesion will cause liquid to remain in contact with the lesion for extended periods. The formulations of the present invention may be applied to treat mucocutaneous lesions in a variety of body compartments, including, but not limited to, the oral cavity, the nasal cavity, the esophagus, the rectum, the bladder, and the vagina.
Furthermore, the viscous, mucoadhesive liquid formulations of the current invention may be used to deliver one or more pharmaceutically active compounds to the mucosal surface, either for the prevention or treatment of diseases and disorders of the mucosa, or for delivery of the pharmaceutically active compound(s) to the systemic circulation by transfer through the mucosa.